This revised grant proposal outlines a five year program for the development of an academic research career in nephrology. The principal investigator (PI) has experience in laboratory investigation and completed nephrology fellowship training. He is currently developing his skills in the investigation of acute kidney injury and the component parts of ischemia and reperfusion . He will receive his primary mentorship from Dr. Keith Hruska, an internationally recognized expert in the field of vascular disease and kidney injury with extensive experience in the training of physician-scientists. Dr. Hruska's expertise will be augmented by a scientific advisory committee comprised of individuals who will provide assistance in defined areas germane to the investigation. The academic environment of the PI's institution has developed substantial resources for the career development of young scientists complemented by a host of core research centers. The research component of this proposal will focus on the RGS4 protein, with known function in the vasculature and inflammatory cells. The renal-specific activity of Regulator of G protein Signaling 4 (RGS4) will be investigated as it applies to ischemia and subsequent reperfusion injury. Ischemia/reperfusion kidney injury is the most common form of acute kidney disease and yet there are few therapeutic options. RGS proteins have the potential to influence the disease process of acute kidney injury, but this area of study is largely unexplored. We hypothesize that RGS4 regulates vasoconstriction during renal ischemia and mitigates the inflammatory response of early renal reperfusion injury. RGS4 has recognized activity in the vascular system. Our findings show RGS4 depletion decreases renal blood flow after acute ischemic injury and is compounded by an early influx of macrophages. Research tools will include genetically modified mouse models that, overexpress RGS4, do not express RGS4 in vascular smooth muscle cells alone, or do not express RGS4 globally. PUBLIC HEALTH RELEVANCE: The overarching goal of this proposal is to better understand how the kidney responds to a loss of blood supply, and how to prevent the subsequent damage that occurs. This is an important topic of study because acute kidney damage affects 15% of all people admitted to hospitals in the United States. This grant proposal coincides with the mandate of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K08 Mentored Clinical Scientist Development Award to encourage the development of promising young physician-scientists in an environment that promotes research excellence in kidney disease.